The present invention provides a novel process for the preparation of substituted piperidin-4-ones useful as intermediates in the preparation of pharmaceuticals.
G. T. Katvalyan and E. A. Mistryukov, Izv. Akad. Nauk SSSR, Ser. Khim., 11, 2575 (2436 transl.) (1968) disclose a multistep synthesis of 1-methyl-3,3-dimethyl-piperidin-4-one starting with methylamine and isobutyraldehyde. In addition, I. V. Micovic, et al., J. Chem. Soc., Perkin Trans., 1, 2041 (1996) disclose a multistep synthesis of 1-benzyl-3,3-gem-dimethyl-piperdine-4-one starting with benzylamine and methyl acrylate.
It has now been discovered that 3-substituted piperidones can be prepared simply and efficiently following the one-pot procedure of the present invention, thus obviating the traditionally lengthy syntheses such as those requiring a Dieckmann condensation.
The present invention provides a process for the preparation of a compound of formula I: 
wherein R is hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, phenyl, benzyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, phenyl, NO2, and CN; R1, R2, R3, R4, R5 and R6 are each independently hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, phenyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94S(C1-C6 alkyl), xe2x80x94S(phenyl), halo(C1-C6)alkyl, phenyl, NO2, and CN; or the pharmaceutically acceptable salt thereof; comprising combining a compound of formula II: 
wherein R1, R2, R3, and R4 are defined as above, a compound of formula III: 
wherein R5 is defined as above, and a compound of formula IV:
Rxe2x80x94NH2xe2x80x83xe2x80x83formula IV
wherein R is defined as above, in the presence of a suitable acid; followed by addition of a suitable base and a compound of formula V: 
wherein R6 is defined as above.
As used herein, the terms xe2x80x9cHaloxe2x80x9d, xe2x80x9cHalidexe2x80x9d or xe2x80x9cHalxe2x80x9d refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein, the term xe2x80x9cMexe2x80x9d refers to a methyl group, the term xe2x80x9cEtxe2x80x9d refers to an ethyl group, the term xe2x80x9cPrxe2x80x9d refers to a propyl group, the term xe2x80x9ciPrxe2x80x9d refers to an isopropyl group, the term xe2x80x9cBuxe2x80x9d refers to a butyl group, the term xe2x80x9cPhxe2x80x9d refers to a phenyl group, the term xe2x80x9cbenzylxe2x80x9d refers to a xe2x80x94CH2phenyl group.
As used herein the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes within its scope xe2x80x9cC1-C4 alkylxe2x80x9d.
As used herein the term xe2x80x9cC1-C6 alkoxyxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term xe2x80x9cC1-C6 alkoxyxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkoxyxe2x80x9d.
As used herein the term xe2x80x9cxe2x80x94S(C1-C6 alkyl)xe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom such as xe2x80x94SCH3, xe2x80x94SCH2CH3, xe2x80x94SCH2CH2CH3, xe2x80x94SCH2CH2CH2CH3, and the like.
As used herein the term xe2x80x9chalo(C1-C6)alkylxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C1-C6)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term xe2x80x9chalo(C1-C6)alkylxe2x80x9d includes within its definition the term xe2x80x9chalo(C1-C4)alkylxe2x80x9d.
This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenyisulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formrate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
The designation  refers to a bond that protrudes forward out of the plane of the page.
The designation  refers to a bond that protrudes backward out of the plane of the page.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, xe2x80x9cStereochemistry of Organic Compoundsxe2x80x9d, John Wiley and Sons, Inc., 1994, Chapter 7 Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
Compounds of formula I can be prepared by following the procedures as set forth in Scheme I. This scheme is not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme I, step A, the compound of formula IV is combined with the compound of formula III in a suitable organic solvent, such as ethanol and the mixture is further combined with a compound of formula II in the presence of a suitable acid. Examples of a suitable acid are inorganic or organic Bronsted acids, which include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, acetic acid, chloroacetic acid, and the like.
For example, about 2.25 equivalents of a compound of formula III is combined with a compound of formula IV in ethanol. This solution is slowly added to a solution of about 1.05 equivalents of compound of formula II in ethanol with about 1.0 to 1.2 equivalents of hydrochloric acid at a temperature of from about 50xc2x0 C. to about 90xc2x0 C., preferably at reflux. After 8 hours to about 24 hours, preferably about 18 hours, in Step B, a suitable base is added followed by addition of about 1 equivalent of compound of formula V. Examples of a suitable base are inorganic or organic bases well known in the art, which include but are not limited to, trialkylamines, such as triethylamine, tributylamine, diisopropylethylamine, isopropyidiethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate tribasic, and the like. Alternatively, when R5xe2x95x90R6, all of the aldehyde can be added in one portion. The reaction is stirred at a temperature of from about 50xc2x0 C. to about 80xc2x0 C., preferably reflux, for about 2 hours to about 16 hours.
The compound of formula I is then isolated and purified using techniques and procedures well known in the art. For example, the reaction mixture is cooled to about 5xc2x0 C. and treated with about one equivalent of base, such as potassium hydroxide dissolved in water. The mixture is then extracted with a suitable organic solvent, such as heptane and MTBE. The organic extracts are then combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula I. The compound of formula I is then purified by recrystallization or flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide purified compound of formula I. Alternatively, the salt of the product can be isolated using standard techniques well known in the art without treating with base.
The following examples represent the process of the present invention as described generally above in Scheme I. These examples are illustrative only and are not intended to limit the invention in any way. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: xe2x80x9ceqxe2x80x9d or xe2x80x9cequiv.xe2x80x9d refers to equivalents; xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cLxe2x80x9d refers to liters; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cmolxe2x80x9d refers to moles; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cpsixe2x80x9d refers to pounds per square inch; xe2x80x9cmm Hgxe2x80x9d refers to millimeters of mercury; xe2x80x9cminxe2x80x9d refers to minutes; xe2x80x9chxe2x80x9d or xe2x80x9chrxe2x80x9d refers to hours; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cRfxe2x80x9d refers to retention factor; xe2x80x9cRtxe2x80x9d refers to retention time; xe2x80x9cxcex4xe2x80x9drefers to part per million down-field from tetramethylsilane; xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran; xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide; xe2x80x9cDMSOxe2x80x9d refers to methyl sulfoxide; xe2x80x9cLDAxe2x80x9d refers to lithium diisopropylamide; xe2x80x9caqxe2x80x9d refers to aqueous; xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate; xe2x80x9ciPrOAcxe2x80x9d refers to isopropyl acetate; xe2x80x9cMeOHxe2x80x9d refers to methanol; xe2x80x9cMTBExe2x80x9d refers to tert-butyl methyl ether; xe2x80x9cTMEDAxe2x80x9d refers to N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, and xe2x80x9cRTxe2x80x9d refers to room temperature.